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Effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive isomer in endotoxic shock in the rat

1983; Wiley; Volume: 78; Issue: 4 Linguagem: Inglês

10.1111/j.1476-5381.1983.tb09426.x

1476-5381

Katherine Anderegg, Peter B. Anzeveno, James A. Cook, Perry V. Halushka, James B. McCarthy, Eugene S. Wagner, W. C. Wise,

Pharmacological Effects of Natural Compounds

We investigated the effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive ortho isomer on arachidonic acid metabolism and pathophysiological sequelae of endotoxic shock. In vehicle‐treated rats, 30 min after intravenous S. enteritidis endotoxin (15 mg/kg), plasma iTxB 2 (the stable metabolite of thromboxane A 2 ) increased from non‐detectable levels (< 100 pg/ml) to 763 ± 250 pg/ml ( n = 10). Plasma i6‐keto‐PGF 1α (the stable metabolite of prostacyclin, PGI 2 ) increased to 1850 ± 426 pg/ml, ( n = 9) and plasma iPGE increased to 2350 = 560 ( n = 5). Pretreatment with the pyridine active (PA) meta isomer (30 mg/kg i.p.) significantly ( P < 0.05) suppressed iTxB 2 to 390 ± 31 pg/ml ( n = 10) although 6‐keto‐PGF 1α levels (1294 ± 358 pg/ml, n = 5) and plasma iPGE (2847 ± 1103 pg/ml, n = 5) were not significantly different from the shocked control values. In contrast, pretreatment with, the pyridine inactive (PI) ortho isomer did not significantly affect endotoxin‐induced iTxB 2 (1431 ± 194 pg/ml, n = 5) or i6‐keto‐PGF 1α synthesis (628 ± 266 pg/ml, n = 5). Pretreatment of rats with the Tx synthetase inhibitor, PA, significantly enhanced ( P < 0.05) survival and prevented splanchnic infarction relative to both endotoxin shocked control rats and those pretreated with the PI isomer. Significantly reduced lysosomal labilization, hepatocellular dysfunction and elevations in serum fibrin/fibrinogen degradation products were seen only in groups pretreated with the PA isomer. The beneficial effects of the latter compound in Endotoxic shock thus appear to be due to inhibition of Tx synthesis, since its ortho isomer did not inhibit TxA 2 synthesis nor did it protect against endotoxic shock.